Indirect comparison and cost-utility of dabigatran etexilate and rivaroxaban in the treatment and extended anticoagulation of venous thromboembolism in a UK setting

Figures & data

Table 1. Acute treatment studies characteristics.

	RE-COVER		RE-COVER II		EINSTEIN-DVT		EINSTEIN-PE
	DBG	WRF	DBG	WRF	RIV	VKA	RIV	VKA
Number of patients	1273	1266	1280	1288	1731	1718	2419	2413
Average age (mean)	55.0	54.4	54.7	55.1	55.8	56.4	57.9	57.5
Caucasian origin	95.2%	94.4%	77.6%	77.6%	n/r	n/r	n/r	n/r
Cancer at baseline	5.0%	4.5%	3.9%	3.9%	n/r	n/r	n/r	n/r
Previous VTE	25.7%	25.4%	19.3%	15.8%	19.4%	19.2%	18.8%	20.3%

DBG, dabigatran; DVT, deep vein thrombosis; RIV, rivaroxaban; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism; WRF, warfarin.

Figure 1. Model diagram. CRNMBE, clinically relevant non-major bleeds; CTEPH, chronic thromboembolic pulmonary hypertension; ICH, intracranial hemorrhage; iDVT, index DVT; iPE, index PE; iVTE, index VTE; MBE, major bleeds; PTS, post-thrombotic syndrome; rDVT, recurrent DVT; rPE, recurrent PE; rVTE, recurrent VTE.

Table 2. Unit costs and resource use inputs, £(2014).

	Unit cost	Resource	Applied in model
Pharmacy costs
RIV 20 mg/day	2.10	day 0–21	2.10
RIV 30 mg/day	4.20	day 22+	4.20
DBG 110/150 mg	1.10	220 mg/day	2.20
Administration costs
Visits - follow-up, DBG	27.99	1 visit	27.99
Visits - follow-up, RIV	27.99	1 visit	27.99
Recurrent events
Acute parenteral anticoagulation PE, outpatient
Pharmacy, average/day			7.78
Administration average/event	5 day	2.13
Acute parenteral anticoagulation DVT, outpatient
Pharmacy, average/day			9.63
Administration average/event	5 day	10.24
Re-treatment after rVTE with WRF
Pharmacy, WRF 4 mg	0.03	4 mg/day	0.07
Visits WRF - initial	62.56	1 visit	62.56
Visits WRF - titration	27.99	4 visits	111.97
Visits WRF - follow-up	27.99	1/month	27.99
Diagnosis recurrent PE event	/event	292
Diagnosis recurrent DVT event	/event	158
Inpatient cost/PE event	250	6.09 day	1369
Inpatient cost/DVT event	168	5.68 day	497
Inpatient cost/ICH event	10,182	/event	10,182
Disabled after ICH		/year	3011
Cost extra-cranial MBE	2357	/event	2357
Cost CRNMBE		/event	396
Cost severe PTS, yr1		/year	442
Cost severe PTS, yr2+	45	2 visits/year	90
Cost CTEPH
Pulmonary endarterectomy	7447	/event	3724
Follow-up cost	1240	/month	1240

CRNMBE, clinically relevant non-major bleeds; DGB, dabigatran; DVT, deep vein thrombosis; ICH, intracranial hemorrhage; IU, international units; kg, kilograms; LMWH, low-molecular weight heparin; MBE, major bleeds; mg, milligrams; PE, pulmonary embolism; PTS, post-thrombotic syndrome; RIV, rivaroxaban; UH, unfractioned heparin; yr, year; assuming a distribution of stroke severity of: 17% mild; 19% moderate; 64% severe.

Table 3. Indirect comparison results—RE-COVER I, II, and EINSTEIN studies.

Treatment group	RR (DBG vs WRF)	RR (RIV vs VKA*)	RR (RIV vs DBG)	Lower CI (RIV vs DBG)	Upper CI (RIV vs DBG)
Recurrent VTE and VTE-related death
Index VTE (DVT + PE)
RIV 3/6/12 months DVT + PE	1.09	0.90	0.83	0.46	1.49
RIV 6 months DVT + PE	1.09	0.98	0.90	0.53	1.52
Extended anticoagulation#	0.08±	0.18±	2.25	0.52	9.69
Index DVT
RIV 3/6/12 months DVT	1.23	0.70	0.57	0.31	1.05
RIV 6 months DVT	1.23	0.86	0.70	0.35	1.39
Index PE
RIV 3/6/12 months PE	0.87	1.13	1.30	0.62	2.70
RIV 6 months PE	0.87	1.13	1.30	0.57	2.94
MCRBE, from start of any treatment
Index VTE (DVT + PE)
RIV 3/6/12 months DVT + PE	0.63	0.94	1.49	1.16	1.92
RIV 6 months DVT + PE	0.63	1.01	1.61	1.18	2.17
Extended anticoagulation#	2.69±	5.19±	1.93	0.69	5.41
Index DVT
RIV 3/6/12 months DVT	0.57	1.00	1.75	1.25	2.50
RIV 6 months DVT	0.57	1.16	2.04	1.39	3.03
Index PE
RIV 3/6/12 months PE	0.75	0.91	1.22	0.83	1.79
RIV 6 months PE	0.75	0.91	1.22	0.80	1.85

CI, confidence interval; DBG, dabigatran; RIV, rivaroxaban; RR, relative risk; VTE, venous thromboembolism; WRF, warfarin.

±vs placebo; *warfarin or acenocoumarol; #based on published indirect comparisons5–7.

Figure 2. Probabilistic sensitivity analyses results. (1a, b) CE plane and CEAC VTE (DVT/PE) treatment; (2a, b) CE plane and CEAC VTE extended anticoagulation; (3a, b) CE plane and CEAC index DVT treatment; (4a, b) CE plane and CEAC index PE treatment; CE, cost-effectiveness; CEAC, cost-effectiveness acceptability curve; DVT, deep vein thrombosis; IC, incremental costs; Incr., incremental; PE, pulmonary embolism; QALY, quality-adjusted life years; VTE, venous thromboembolism.

Table 4. Deterministic analyses results: 6 months dabigatran vs 3-6-12 months rivaroxaban.

	VTE treatment			VTE treatment and extended anticoagulation
	DBG	RIV	Incr.	DBG	RIV	Incr.
Events per 10,000 patients
All recurrent VTE	12,683	12,641	42	12,542	12,542	1
Symptomatic recurrent non-fatal VTE events	11,248	11,208	40	11,128	11,130	−2
Non-fatal DVT	8254	8182	72	8162	8122	40
Non-fatal PE	2995	3026	−32	2965	3007	−42
VTE-related death	1435	1433	2	1414	1412	3
All major and clinically relevant bleeds	1037	1296	−260	1471	2189	−718
Non-fatal major and clinically relevant bleeds	1028	1286	−258	1462	2178	−716
Intracranial hemorrhage	19	22	−3	19	22	−3
Other major bleeds	235	168	68	259	267	−8
Clinically relevant non-major bleeds	774	1096	−322	1184	1890	−705
Deaths from bleeding	9	10	−2	9	10	−2
PTS	1252	1246	6	1244	1241	3
CTEPH	236	237	−1	234	236	−1
Discounted^a QALY (mean per patient) (CI)	12.406 (12.09–12.65)	12.404 (12.10–12.63)	0.002 (−0.02–0.03)	12.430 (12.17–12.67)	12.421 (12.15–12.64)	0.009 (−0.01–0.07)
Total costs, mean per patient (£) (CI)	7474 (4619–11,122)	7510 (4672–11,209)	−27 (−145–77)	7757 (4862–11,778)	7830 (4912–11,866)	−74 (−301–40)
Drug costs (£)	461	461	0	776	772	4
Monitoring costs (£)	370	364	6	363	357	6
Event costs (£)	6643	6686	−43	6617	6700	−83
ICER, costs/QALYs			dominant			dominant
	Index DVT			Index PE
Events per 10,000 patients
All recurrent VTE	12,676	12,573	103	12,696	12,755	−59
Symptomatic recurrent non-fatal VTE events	11,245	11,144	101	11,250	11,310	−60
Non-fatal DVT	8292	8167	125	8132	8209	−77
Non-fatal PE	2953	2976	−24	3118	3101	17
VTE-related death	1431	1429	1	1447	1445	2
All major and clinically relevant bleeds	984	1343	−359	1154	1297	−144
Non-fatal major and clinically relevant bleeds	975	1332	−357	1147	1287	−141
Intracranial hemorrhage	21	24	−3	15	18	−3
Other major bleeds	258	181	76	187	151	36
Clinically relevant non-major bleeds	696	1127	−431	945	1119	−174
Deaths from bleeding	9	11	−2	7	10	−3
PTS	1510	1499	10	686	693	−7
CTEPH	114	115	−1	501	500	1
Discounted^a QALY (mean per patient) (CI)	12.403 (12.14–12.66)	12.400 (12.14–12.65)	0.003 (−0.02–0.03)	12.409 (12.14–12.66)	12.404 (12.14–12.64)	0.005 (−0.04–0.06)
Total costs, mean per patient (£) (CI)	3798 (2855–5139)	3818 (2873–5186)	−20 (−166–89)	15,509 (8,353–25,834)	15,514 (8,369–26,021)	−5 (−253–179)
Drug costs (£)	465	463	2	453	460	−7
Monitoring costs (£)	374	365	9	361	361	0
Event costs (£)	2959	2990	−31	14695	14,693	2
ICER, costs/QALYs			dominant			dominant

Incr., Incremental; CRNMBE, clinically relevant non-major bleeds; CTEPH, chronic thromboembolic pulmonary hypertension; DBG, dabigatran; DVT, deep vein thrombosis; ICER, incremental cost-effectiveness ratio; ICH, intracranial hemorrhage; ICUR, incremental cost-utility ratio; MBE, major bleeds; PE, pulmonary embolism; QALYs, quality-adjusted life years; VTE, venous thromboembolism; WRF, warfarin; ^adiscounted at 3.5% annual rate; CI, 95% confidence interval (obtained from probabilistic sensitivity analysis).

Table 5. Deterministic analyses results: 6 months dabigatran vs 6 months rivaroxaban.

	VTE treatment			VTE treatment and extended anticoagulation
	DBG	RIV	Incr.	DBG	RIV	Incr.
Events per 10,000 patients
All recurrent VTE	12,683	12,656	27	12,542	12,556	−14
Symptomatic recurrent non-fatal VTE events	11,248	11,223	25	11,128	11,145	−17
Non-fatal DVT	8254	8194	60	8162	8134	28
Non-fatal PE	2995	3029	−35	2965	3010	−45
VTE-related death	1435	1433	2	1414	1412	3
All major and clinically relevant bleeds	1037	1360	−323	1471	2255	−785
Non-fatal major and clinically relevant bleeds	1028	1349	−320	1462	2244	−782
Intracranial hemorrhage	19	21	−3	19	21	−3
Other major bleeds	235	176	60	259	275	−16
Clinically relevant non-major bleeds	774	1151	−377	1184	1948	−763
Deaths from bleeding	9	11	−3	9	11	−3
PTS	1252	1247	5	1244	1242	2
CTEPH	236	237	−1	234	236	−2
Discounted^a QALY (mean per patient) (CI)	12.406 (12.12–12.65)	12.402 (12.12–12.64)	0.005 (−0.02–0.03)	12.430 (12.15–12.68)	12.419 (12.12–12.66)	0.012 (−0.01–0.08)
Total costs, mean per patient (£) (CI)	7474 (4888–12,104)	7519 (4740–11,610)	−45 (−187–53)	7757 (4940–12,026)	7847 (5007–12,178)	−91 (−330–29)
Drug costs (£)	461	461	0	776	774	2
Monitoring costs (£)	370	364	6	363	358	6
Event costs (£)	6643	6694	−51	6617	6716	−99
ICER, costs/QALYs			dominant			dominant
	Index DVT			Index PE
Events per 10,000 patients
All recurrent VTE	12,676	12,601	75	12,696	12,755	−59
Symptomatic recurrent non-fatal VTE events	11,245	11,171	74	11,250	11,310	−60
Non-fatal DVT	8292	8178	115	8132	8209	−77
Non-fatal PE	2953	2993	−41	3118	3101	17
VTE-related death	1431	1430	1	1447	1445	2
All major and clinically relevant bleeds	984	1478	−494	1154	1297	−144
Non-fatal major and clinically relevant bleeds	975	1466	−491	1147	1287	−141
Intracranial hemorrhage	21	25	−5	15	18	−3
Other major bleeds	258	192	65	187	151	36
Clinically relevant non-major bleeds	696	1249	−552	945	1119	−174
Deaths from bleeding	9	12	−3	7	10	−3
PTS	1510	1500	10	686	693	−7
CTEPH	114	116	−2	501	500	1
Discounted^a QALY (mean per patient) (CI)	12.403 (12.12–12.64)	12.394 (12.12–12.64)	0.009 (−0.02–0.05)	12.409 (12.13–12.67)	12.404 (12.11–12.67)	0.005 (−0.05–0.05)
Total costs, mean per patient (£) (CI)	3798 (2857–5236)	3854 (2898–5350)	−57 (−235–67)	15,509 (8145–25,571)	15,514 (8166–25,527)	−5 (−290–188)
Drug costs (£)	465	461	3	453	460	−7
Monitoring costs (£)	374	365	9	361	361	0
Event costs (£)	2959	3028	−69	14,695	14,693	2
ICER, costs/QALYs			dominant			dominant

Incr., Incremental; CRNMBE, clinically relevant non-major bleeds; CTEPH, chronic thromboembolic pulmonary hypertension; DBG, dabigatran; DVT, deep vein thrombosis; ICER, incremental cost-effectiveness ratio; ICH, intracranial hemorrhage; ICUR, incremental cost-utility ratio; MBE, major bleeds; PE, pulmonary embolism; QALYs, quality-adjusted life years; VTE, venous thromboembolism; WRF, warfarin; ^adiscounted at 3.5% annual rate; CI, 95% confidence interval (obtained from probabilistic sensitivity analysis).